This is the first randomized controlled comparison of inflammatory markers between therapy with quadruple-dose rosuvastatin and rosuvastatin combined with ezetimibe when both methods similarly reduced LDL-C. We assumed based on previous findings[18–20] that both R10 and R2.5/E10 would equally reduce LDL-C. We found that both treatments indeed similarly reduced LDL-C as well as T-Cho, TG, LDL-C/HDL-C ratio and MDA-LDL after 12 weeks. However, HDL-C was significantly improved in the R10, compared with the R2.5/E10 group. Changes in inflammatory markers between the two groups did not significantly differ. Only HDL-C among all tested parameters significantly differed between the two groups. We included patients who had hs-CRP > 1.0 mg/L despite treatment with rosuvastatin 2.5 mg. The cut-off value was defined as hs-CRP > 1.0 mg/L based on the population-based, prospective, cohort Hisayama study, which demonstrated that hs-CRP > 1.0 mg/L is the cut-off for a high risk of future CAD development in the general Japanese population. This value is much lower than the hs-CRP value of >3.0 mg/L that corresponds to a high risk for future cardiovascular events in non-Japanese populations. None of the participants in both of these studies were taking statins. The PATROL trial compared the safety and efficacy of atorvastatin, rosuvastatin and pitavastatin head-to-head in patients with hypercholesterolemia and found that hs-CRP after treatment with rosuvastatin 2.5 mg was 1.1 ± 2.0 mg/L in Japanese patients with CAD. This suggested that very few of our patients had hs-CRP > 3.0 mg/L after treatment with rosuvastatin 2.5 mg. Therefore, our cut-off of hs-CRP > 1.0 mg/L was reasonable for our participants.
A simvastatin study with a similar protocol to the present study found no significant improvements in hs-CRP and IL-6. Likewise, changes in inflammatory markers did not significantly differ between R10 and the R2.5/E10 in the present study, in which the protocol was designed so that both strategies would similarly reduce LDL-C. The findings of the present and simvastatin studies suggest that the anti-inflammatory effects and the LDL-C reductions do not significantly differ between a quadruple dose of any statin and the addition of ezetimibe.
We found that both strategies significantly reduced hs-CRP, although pro-inflammatory cytokines did not significantly differ between baseline and 12 weeks later. Some small-scale studies have found that statins significantly reduce IL-6 and TNF-α[26, 27]. On the other hand, the population-based Colaus study that examined associations between statins and hs-CRP, IL-6 and TNF-α in 6,184 patients, found lower hs-CRP levels in those treated with, than without statins, and that statins did not elicit any effects on IL-6 and TNF-α levels in the patients. The present and Colaus studies showed that statins decrease hs-CRP without affecting pro-inflammatory cytokines. The reason for the discrepancy between hs-CRP and pro-inflammatory cytokines remains undetermined. More recently, another study found that neither high-dose simvastatin nor low-dose simvastatin combined with ezetimibe reduce proinflammatory markers such as IL-6. In addition, several studies in vitro have demonstrated a direct effect of statins on IL-6 induced hs-CRP expression in human hepatocytes[30–32]. Although the anti-inflammatory effect of ezetimibe monotherapy has been controversial, our results suggest that R10 and R2.5/E10 can decrease hs-CRP through mechanisms that are independent of the IL-6 receptor.
The present study showed that the novel inflammatory marker PTX3, which is a member of pentraxin superfamily like hs-CRP, did not significantly differ between plasma levels at baseline and at 12 weeks after randomization. By contrast, other studies have shown that statin therapy significantly decreases PTX3 levels[34, 35]. One possible explanation for the discrepancy is that the baseline PTX3 concentration was similar to the average in healthy volunteers. The plasma PTX3 concentration might have been fully decreased in our patients at the time of enrolment in the present study, because they had already been treated with rosuvastatin (2.5 mg/day) for at least 4 weeks before randomization.
The results of the present study were similar to those of a comparison of atorvastatin (10 mg/day) with atorvastatin (10 mg/day) combined with ezetimibe (10 mg/day) in patients with CAD in that the combination significantly decreased hs-CRP, but not PTX3. Therefore, adding ezetimibe might not decrease PTX3 in the manner of hs-CRP.
The present study found that R10 significantly increased HDL-C by 6.9% (1.8% - 15.1%) from baseline compared with R2.5/E10. Our results were similar to those of a meta-analysis in the VOYAGER study, which showed that rosuvastatin (10 mg/day) increases HDL-C by 6.1 ± 0.5% from baseline. In contrast, others have found that adding ezetimibe does not significantly increase HDL-C from baseline[25, 39, 40]. Therefore, these results suggest that increasing the dose of statin elevates HDL-C more effectively than adding ezetimibe. The TNT trial of individuals in whom atorvastatin decreased LDL-C to <70 mg/dL showed that low HDL-C levels remain as independent predictors of CAD risk even in patients with low LDL-C. Both R10 and R2.5/E10 decreased LDL-C to <70 mg/dL in the present study, as in the TNT trial, and the only significant difference was HDL-C between the two groups. The clinical benefit of increasing HDL-C using antidyslipidemic agents was controversial. According to the recent trial, cholesteryl ester transfer protein inhibitor which increased HDL-C levels 31 to 40% did not improve clinical outcome in patients with CAD. However, another trial of the clinical value of increasing HDL-C using statin found that a change in the HDL-C level was a powerful independent risk factor for cardiovascular events. Although the clinical value of increasing HDL-C was undetermined, these trials suggested that statins had characteristic effects to improve both HDL-C levels and clinical outcomes. Thus, our results might reflect the difference in clinical outcomes between high-dose rosuvastatin monotherapy and the combination of ezetimibe and rosuvastatin.
The lack of additional benefits of ezetimibe beyond LDL-C and hs-CRP lowering might partly explain the findings of ENHANCE study in which ezetimibe, when added to a statin, did not alter the progression of carotid artery intima-media thickening despite a further reductions in LDL-C and in inflammatory biomarkers such as hs-CRP compared with statins alone. Although the patients enrolled in the ENHANCE study had relatively low levels of carotid artery intima-media thickening and a correlation between carotid artery intima-media thickening change and cardiovascular outcome was not investigated, adding ezetimibe to statin did not reduce carotid artery intima-media thickness. On the other hand, others have shown that statins cause carotid intima-media thickness to regress[45, 46]. According to these and the present findings, quadruple-dose statin might be more favourable than a combination of ezetimibe and statin at least from the viewpoint of an anti-atherogenic effect.
The present study has several limitations. Firstly, statistical power was low because we sampled only 46 patients, of whom only a few had hs-CRP > 1.0 mg/L while taking 2.5 mg/day of rosuvastatin. However, the findings of this exploratory pilot study were meaningful for planning a future large-scale study. Secondly, since all the patients were Japanese and because the cut-off for a high risk of CAD development is lower for Japanese than for other patients, ethnic variation should be taken into account when considering changes in inflammatory markers. Thirdly, this open label, but not double-blind, study examined surrogate endpoints of lipid profiles and inflammatory markers and did not measure any actual clinical outcomes. Further prospective long-term large clinical trials are needed to define the effects of statins and ezetimibe on clinical outcomes.